2-alkylamino benzophenones

ABSTRACT

WHEREIN; R1 is hydroxyl, 1,2-dihydroxyethyl, O-sulfate sodium salt, carbamoyloxy, N-lower-alkyl-carbamoyloxy, N,N-di-lower-alkylcarbamoyloxy, 2-oxazolidinon-5-yl, and 3-lower-alkyl-2oxazolindinon-5-yl, R2 is hydrogen, lower-alkyl and carbethoxy, R3 is halogen, hydrogen, alkoxy, nitro and trifluoromethyl, and N IS ZERO, ONE AND TWO. The compounds have mild CNS depressant tranquilizing and pepsin inhibition activities.   Novel 2-alkylaminobenzophenones are described having the formula:

United States Patent [191 Welstead, Jr. et al.

[ Nov. 5, 1974 Z-ALKYLAMINO BENZOPHENONES [73] Assignee: A. H. Robins Company,

Incorporated, Richmond, Va.

[22] Filed: Sept. 20, 1972 [21] Appl. No.: 290,568

[52] US. Cl. 260/482 C, 260/307 C, 260/556 AR, 260/570 AB, 424/272, 424/300, 424/330 UNITED STATES PATENTS ll/l97l Duennenberger et al. 260/471 C 8/1973 Topliss 260/326 N Primary ExaminerG. Thomas Todd [57] ABSTRACT Novel 2-alkylaminobenzophenones are described having the formula:

wherein;

R is hydroxyl, 1,2-dihydroxyethyl, O-sulfate sodium salt, carbamoyloxy, N-lower-alkyl-carbamoyloxy, N,N-di-lower-alkyl-carbamoyloxy, 2-oxazolidinon-5-yl, and 3-lower-alkyl-2-oxazolindinon-S y], I V

R is hydrogen, lower-alkyl and carbethoxy,

R is halogen, hydrogen, alkoxy, nitro and trifluoromethyl, and

n is zero, one and two.

The compounds have mild CNS depressant tranquilizing and pepsin inhibition activities.

4 Claims, No Drawings 2-ALKYLAMINO BENZOPHENONES The present invention relates to novel 2- aminobenzophenones and is particularly concerned with 2-alkylamino-5-substituted benzophenones, compositions thereof and methods of making and using same.

The invention is especially concerned with novel compounds having the formula:

N-( CH; -R Formula I niques in Drug Evaluation, Vol. I, pp. 36-54). Certain of the compounds are useful as tranquilizing agents. They are active in mice and rats in intraperitoneal doses of 5-50 mg./kg. when evaluated in the standard test procedure in which animals are administered a compound and observed for behavioral effects. Compounds of the invention preferred for their tranquilizing action are 5-chloro-2-[N-(2,3-dihydroxypropyl)-N- methylamino1benzophenone and 5-chloro-2-[N- carbethoxy-N-( 2-hydroxyethyl laminobenzophenone. Some of the compounds also exhibit inhibition of pepsin proteolysis useful in gastroenterology as determined by the method of Mett (Hawk, B. P., Oser, B. L., and Summerson, W. H.: Practical Physiological Chemistry, McGraw-Hill, New York, 1951 p. 374).

Lower-alkyl as used in the foregoing Formula I and where it appears elsewhere throughout the specification and claims thereof includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, heptyl, octyl, andthe like.

The starting materials of Formula II for preparing the compounds of Formula I are the tosylamidobenzophenone derivatives of the 5-substituted -2- aminobenzophenones which are prepared according to the method described by Bell, S. C. et al., J. Org. Chem. 27, 562-566 (1962).

The following Chart I illustrates the synthetic methods used to prepare the compounds of the invention represented in- Formula I.

CHART I a a (l) NaH R H R H Me (2). A (see Note) l l (3) 80% H2504 2) N-SOg f c=o I I II CBHS e s (1) NaH (1) HCOOH HCHO, (2) Halo (CH OH or (3) Cone. so (2) c n ococl (4) NaOH R" F Re I N -(CH OSO Na c=o I I CgHg 6H5 B (See Note) 2' Note: R

is w-haloalkanol. l-halomethylethyleneglycol, 5-halomethyl-2-oxazolidinone (2-haloethyI)-2-oxazolidinone. B is NaOCN, lower-alkyl-isocyanate or N,N-dilower-alkylcarbamoyl halide.

.N-( C 2 -n or 3-methyl-5- C l-I 3 4 Compounds of Formula I wherein R is hydrogen are 2-( 2-hydroxyethylamino)-benzophenone, prepared by reacting a compound of Formula II succes- 5-methoxy-2-(Z-hydroxyethylamino)-benzophenone, sively with sodium hydride and a compound having a reactive halide and then hydrolyzing the mixture using 5-nitro-2-(2-hydroxyethylamino)-benzophenone, 80% sulfuric acid to remove the tosyl moiety. When 5 and one of the reactants is an w-haloalkanol, substitution of 5-triflu0r0methyl-2-(2-hydroxyethylamino)benconcentrated sulfuric acid in the hydrolysis step for zophenone. 80% sulfuric acid followed by neutralization of the hydrolysis mixture leads to the sulfonation of the alcohol Example 2 and the sulfate alkali metal Saltto -Chloro-2-(2-hydroxyethyl)aminobenzophenone,

, The preparation of compounds wherein R is methyl 0-sulfate sodium salt is accomplished by reaciing t sepqndary amine with A stirred mixture of 50 g. (0.13 mole) of 5-chloro-2- l gl and fol-mm Slm'larly comPounds tosylamidobenzophenone in 50 ml. of dimethylformwherem R Farbephoxy are prepared by reactmg the amide was added dropwise to a mixture of 6 g. (0.13 Secondary amme l 2Y if mole) of sodium hydride 54% in mineral oil) in 100 Compounds wherem R .methyl and R hydroxy] ml. of dimethylformamide. After hydrogen evolution can be further reaqted cyanates and lower had ceased and the mixture was treated with 16.5 g. alkylcarbamoyl q to produce compounds of (0.13 mole) of bromoethanol and heated at 8090C. Formula I wherein R1 ls (larbamoyloxy N'lower'alkyl' overnight the mixture was poured into water and the carbamoyloxy and NN'd"lower'alkyl'carbampyloxy' resulting gummy solid was dissolved in 200 ml. of con- The following examples are presented to illustrate centmted H2804y heated on a Steam bath for 30 i g g a of i g g g p qi l y l li utes, then diluted with 500 ml. of water. The resulting an t ey S no e cons me as 1m] mg l m 5pm gum was extracted with low boiling petroleum ether to or in Scope remove the mineral oil, then the mixture was made al- Example 1 kaline with 6N sodium hydroxide. A benzene extraction gave an emulsion which broke on addition of sev- 5-Chlor0'2'(Z'hydroxyethyl)ammobenzophenone eral ml. of methanol. Evaporation of the extract gave T0 12 gmole) of 54% Sodium y ride in 10 g. of crude starting material. The aqueous layer was era] oil and 200 ml. of dried dime hylf rm mi Was re-extracted with benzene and 5 ml. of butanol was added 100 8- mole) of I 30 used to break the emulsion. Three layers formed. The tosylamidobenzophenone P p from viscous middle layer was separated and triturated with chlorobenzophenone in 100 ml. of dried dimethylformbenzene to yield a solid. Recrystallization from 95% alamide. After the evolution of hydrogen ceased, the cohol gave 27 g. (51%) of water soluble product which mixture was stirred for an additional hour followed by melted above 180C. with decomposition. The undried the addition of 33 g. (0.26 mole) of 2-bromoethanol. sample analyzed as a hydrate.

Analysis: Calculated for C H CINaNO S C,47.69; H,3.47; N,3.7l Found :C,47.15; H.359; N,3.79 Calculated for C H CINaNO S C,45.52; H.382; N,3.54

(Hydrate) Found :C,44.78; H,3.70; N3 50 The resulting mixture was heated while stirring at 95C. Using the procedure of Example 2 and replacing 5- for 12 hours. The reaction mixture was then poured chloro-2-tosylamidobenzophenone with equal molar into one liter of water and extracted with benzene. The amount of extracts were dried over magnesium sulfate and con- 2-tosylamidobenzophenone, centrated on a rotating evaporator. The resulting oil 5-methoxy-2-tosylamidobenzophenone, was dissolved in 300 ml. of 80% sulfuric acid and 5-nitro-2-tosylamidobenzophenone, heated on a steam bath for one hour. The mixture, after 5-trifluoromethyl-2-tosylamidobenzophenone, being cooled, was extracted with petroleum ether to rethere are obtained move the mineral oil then neutralized with 6N sodium 2-( 2-hydroxymethyl)amino-benzophenone O-sulfate hydroxide. The resulting product was extracted into sodium salt, benzene, dried over magnesium sulfate, then evapo- 5-methoxy-2-(2-hydroxymethyl)amino benzopherated to an oil. The product crystallized on standing none O-sulfate sodium salt, and was recrystallized from ligroin, yielding 26 g. 5-nitro-2-(2-hydroxymethyl)amino benzophenone (35%) of product; melting at 8l-83C. O-sulfate sodium salt,

Analysis Calculated for CNHHCINOI C,65.34; H.5.l2'. N,5.08 Found :C,65.13; H,5.03; N,5.l9

Using the procedure of Example 1 and replacing 5- 5-trifluoromethyl-2-(2-hydroxymethyl)aminobenchloro-2- tosylamidobenzophenone with zophenone O-sulfate sodium salt. 2-tosylamidobenzophenone, 5-methoxy-2-tosylamidobenzophenone, Example 3 5-nitro-2-tosylamidobenzophenone, and 5-trifluoromethyl-2-tosylamidobenzophenone, 5-Chl0ro-2-(2,3-dihydroxypropylamino)benzophethere are obtained none.

A solution of 39 g. (0.1 mole) of 5-chloro-2- tosylamidobenzophenone in 40 ml. of dimethylformamide was added to a suspension of 2.6 g. (0.11 mole) of sodium hydride in 70 ml. of dimethylformamide. After the evolution of hydrogen ceased, the mixture was stirred for an additional half hour. To the reaction t e as dded 11 mo e) Q .3-9 9r02 pane-1,2-diol in 40 ml. of dimethylformamide and the mixture was heated at 90C. with stirring for 72 hours. The mixture was poured into water and extracted with benzene. The benzene extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was then dissolved in 500 ml. of 80% sulfuric acid and heated on a steam bath for 4 hours. After cooling, the acid mixture was carefully neutralized with 6N sodium hydroxide and extracted with benzene. The benzene extracts were washed with water, dried over magnesium sulfate and evaporated under remole) of 5-chloro-2-tosylamidobenzophenone in ml. of dimethylformamide. After evolution of hydrogen had ceased, the mixture was warmed to room temperature and treated with 8.5 g. (0.502 mole) of 3-methyl- 5-(2-chloroethyl)-2-oxazolidinone in 20 ml. of dimethylformamide. The reaction mixture was heated at 90C. with stirring for 12 hours, then poured into water. The product was extracted into benzene and the extract was evaporated to yield 16 g. of oil. The oil was dissolved in 100 ml. of concentrated sulfuric acid by warming; then the mixture was cooled, made basic with 3N sodium hydroxide and the product extracted into benzene. After drying over magnesium sulfate, the benzene extracts were chromatographed on 400 g. of magnesium silicate using benzene-acetone to elute. From the column, 5 g. (23%) of pure oily product was obtained. A sample was molecularly distilled for analysis.

Analysis: Calculated for C H CIMO C,63.42; H560; N,7.79 Found :C,63.68; H,5.57; N,7.84

Example 6 duced pressure to an oil. The crude oil (14 g.) was placed on a 400 g. magnesium silicate column and eluted with benzene-acetone. The purified product, 4.5 25 g. (15%) solidified on standing and was recrystallized from ethyl-ether, m.p. 118-120C.

5-Chloro-2-[ N-( 2-hydroxyethyl )-N- methylamino]benzophenone.

To 11 g. (0.2 mole) of 97% formic acid solution at 0C. was added 20 g. (0.07 mole) of 5-chloro-2-(2- Analysis: Calculated for C H ClNO C,62.8S; H,5.27; N.4.58 Found C.63.46; H,5.30; N.4.77

Example 4 5-Chloro-2-(2-oxazolidinon-5-ylmethylamino)- benzophenone To a stirred mixture of 1.3 g. (0.05 mole) of sodium hydride in 20 ml. of dimethylformamide was added 20 g. (0.05 mole) of 5-chloro-2-tosylamidobenzophenone 40 in 20 ml. of dimethylformamide. After the evolution of hydrogen had subsided, 9.4 g. (0.05 mole) of 5-bromomethyl-2-oxazolidinone was added and the mixture was stirred at 8090C. for 24 hours. The mixture was poured into water and the resulting gummy Analysis:

Calculated for C H CINO Found solid was filtered off and redissolved in 100 ml. of con-. centrated sulfuric acid. After stirring 1 hour, the mixture was cooled and made basic with 3N sodium hydroxide. The product was extracted from the mixture with benzene and the extract was dried over magnesium sulfate and evaporated to an oil (14 g.). Chromatography on 300 g. of 60-100 mesh magnesium silicate using benzene-acetone to elute gave 7 g. (59%) of solid which melted at l57-159C. after recrystallization from benzene-isooctane.

Using the procedure of Example 6 and replacing 5- chloro-2-(2-hydroxyethyl)amine benzophenone with 2-(2-hydroxyethyl)aminobenzophenone, and 5-methoxy-2-(2-hydroxyethyl)aminobenzophenone,

there are obtained 2-[N-(2-hydroxyethy1)-N- methylamino]benzophenone, and 5-methoxy-2-[N-( 2-hydroxyethyl)-N- Anal sis: Calculated forC H CINO :C.6l.

y 11 ll a a CM GG;

HA Found H 4 methylamino]benzophenone.

Example 5 S-Chloro-Z-i 2-( 3-methyl-2-oxazolidinon-5- yl)ethylamino]benzophenone To 0.06 mole of sodium hydride in 40 ml. of dimethylformamide at 0C. was added dropwise 20 g. (0.052

Example 7 5-Chloro-2-(N-2,3-dihydroxypropyl-N- methylamino)benzophenone.

A mixture of 16 g. (0.052 mole) of 5-chloro-2-(2,3- dihydroxypropylamino)benzophenone and 13.4 g.

(0.26 mole) of formic acid was heated until all the starting material dissolved. The mixture was cooled, treated with 7.05 g. (0.157 mole) of 37% formaldehyde solution and then heated to reflux. After refluxing overnight, the mixture was cooled, poured into water and extracted with benzene. The benzene extracts were Analysis:

Calculated for C I-I CINO C,63.85; H 5.67; N,4.38 Found :C,63.54; H564; N,4.39

Example 8 -Chloro-2-[N-methyl-N-2-(3-methyl-2-oxazolidinon- 5 -yl )ethylamino -benzophenone A mixture of 8 g. (0.02 mole) of 5-chloro-2-[2-(3- methyl-2-oxazolidinone-5-yl)ethylamino]benz0phenone and 5.1 g. (0.09 mole) of 89% formic acid solution was heated until all the starting material dissolved. The mixture was cooled and treated with 8 ml. (0.067 mole) of 37% formaldehyde solution. After refluxing for 18 hours, the reaction mixture was cooled, poured into water and extracted with benzene. The benzene extracts were washed with water, dried over magnesium sulfate and evaporated to an oil. The crude oil was dissolved in ether, treated with ethereal HCl and the resulting solid was triturated several times with dry ether. The purified salt was converted back to the free base and molecularly distilled for analysis. The yield of purified product was 5 g. (60%).

Calculated for cgnHmclNgoa Analysis:

, Found Example 9 5-Chloro-2-[N-Carbethoxy-N-( 2-hydroxyethyl ]aminobenzophenone A solution of 12 g. (0.043 mole) of 2-(2- hydroxyethylamino)-5-chlorobenzophen0ne in 50 ml.

of water and 25 ml. of dioxane was treated with g.

Calculated for C H CINO Analysis:

Found Example 10 5-Chloro-2-[N-(Z-carbamoyloxyethyl)-N- methylamino]benzophenone A slowly stirred mixture of 7 g. (0.024 mole) of 5- chloro-2-[N-(2-hydroxyethyl)-N- methyl]aminobenzophenone and 3.15 g. (0.05 mole) of sodium cyanate and 50 ml. of methylene chloride was treated dropwise with 4.3 g. (0.05 mole) of trifluoroacetic acid. After stirring overnight at room temperature, an additional 1.57 g. (0.025 mole) of sodium cyanate and 2.15 g. (0.025 mole) of trifluoroacetic acid was added and the mixture was allowed to stir an additional 12 hours. The mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and evaporated to an oil. The crude oil was chromatographed on 200 g. of 60-l00 mesh magnesium silicate and eluted with benzene-acetone. Yield of purified product was 3 g. (38%). A sample was molecularly distilled for analysis.

Analysis: i( ialctijlated for C H CIN Q-I,

oun

Example 1 l 5-Chloro-2-[N-(Z-dimethylcarbamoyloxyethyl)-N- methylamino]benzophenone A mixture of 4 g. (0.014 mole) of 5-chloro-2-[(N-2- hydroxyethyl)-N-methyl]aminobenzophenone and 1.5 g. (0.014 mole) of dimethylcarbamoyl chloride in 25 ml. of pyridine was refluxed for 24 hours. The mixture was poured into water, acidified with concentrated hydrochloric acid and extracted with benzene. The benzene extracts were washed with water, dried over magnesium sulfate and evaporated to an oil. The crude oil was chromatographed on 175 g. of 60-100 mesh magnesium silicate and eluted with benzene-acetone. The yield of purified product was 3.5 g. A sample was molecularly distilled for analysis.

Calculated for c u cm o,

Analysis:

Found s R R l 2) nam- R wherein:

carbamoyloxyethyl)-N-methylamino]benzophenone.

3. A compound of claim 1 which is 5-chloro-2-[N-(2- dimethylcarbamoyloxyethyl)-N-methylamino]benzophenone.

4. A compound of claim 1 which is 5-chloro-2-[N-(2- butylcarbamoyloxyethyD-N-methylamino]benzophe- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 77 Dated Nov. 5, 197M Inventor) William J. Welstead, Jr. and Harold F. Stauffer, Jr.

It is certified that error appears in the above-identified patent Q and that said Letters Patent are hereby corrected as shown below:

Column 8, lines 56 to 66, formula should appear as shown below instead of as in the patent:

2 R I 2)n- C=O I Signed and Scaled this seventh Day of October 1975 [SEAL] Arrest:

v RUTH C. MASON C. MARSHALL DANN Arresting Officer. Commissioner uj'larents and Trademarks 

1. A COMPOUND SELECTED FROM 2-ALKYLAMINOBENZOPHENONES HAVING THE FORMULA:
 2. A compound of claim 1 which is 5-chloro-2-(N-(2-carbamoyloxyethyl)-N-methylamino)benzophenone.
 3. A compound of claim 1 which is 5-chloro-2-(N-(2-dimethylcarbamoyloxyethyl)-N-methylamino)benzophenone.
 4. A compound of claim 1 which is 5-chloro-2-(N-(2-butylcarbamoyloxyethyl)-N-methylamino)benzophenone. 